1. Field of the Invention
The present embodiments relate to methods for the treatment of autoimmune or immune related diseases or disorders. More specifically the present embodiments relate to sulfatides for use in the treatment of autoimmune or immune related diseases or disorders.
2. Description of the Related Art
Autoimmune diseases effect millions of people worldwide and can have devastating effects on lifespan and quality of life. Despite advances in medical science, many autoimmune diseases have evaded treatment because the mechanisms of disease are complex and poorly understood. Also, unlike most diseases where treatment involves working with the body's immune system to combat a foreign invader, in autoimmune diseases, the immune system itself is exacerbating the problem. This makes any treatment much more difficult because it must address the immune response directly to combat the problem.
In multiple sclerosis, for example, the immune system pathologically recognizes some self-antigens from myelin membranes as foreign and initiates an immune response against them. This results in demyelination, the destructive removal of myelin which is an insulating and protective fatty protein that sheaths nerve cells (neurons). The demyelination in multiple sclerosis is mediated by a T-cell guided immune response that is either initiated from antigen-presenting events in the CNS or induced following the peripheral activation by a systemic molecular mimicry response.
Experimental autoimmune encephalomyelitis (EAE) is a prototypic T-cell mediated autoimmune disease, characterized by inflammation and demyelination in the central nervous system accompanied by paralysis following immunization with myelin antigens, for example, myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein (PLP). EAE shares many pathological and immune dysfunctions with human MS and is a widely accepted model for studying human MS.
Glycolipids can be recognized by T cells in the context of class I MHC-like cell surface proteins known as CD1. Myelin is a rich source of glycolipids, and myelin is the target of an autoimmune process during EAE in which the influence of myelin-derived lipids and their presentation to T cells in the CNS can be easily studied. In order to derive effective treatments for multiple sclerosis, further characterization of glycolipid-reactive T cells is needed. Sulfatide is one of the major glycolipids in myelin and has been shown to bind to CD1d. (Jahng, et al. J. Exp. Med. Vol. 199 Num. 7: 947-957, 2004.)
In AIDS, T-cells are systematically depleted by the HIV virus. Like with many autoimmune diseases, the immune system itself tends to advance the disease because the virus is spread through immune cells. Human immunodeficiency virus (HIV) infects CD4+ cells in conjunction with a cellular coreceptor, CXCR4, or CCR5/CCR3. HIV infection of human cells results in loss of CD4+ T lymphocytes as the virus undergoes rapid replication generating mutations in its envelope region of the viral genome. These also include drug resistant mutants as the infected individuals are treated with antiretroviral drugs including zidovudine (AZT), nucleoside reverse transcriptase inhibitor (NRTI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor. Further, there is an exhaustion of the cytotoxic T lymphocytes and the eventual failure of the immune system, both cell mediated and humoral responses, of the infected individual to fight the infection arising from the generation of multiple HIV strains in vivo. The immune system is also exacerbated due to opportunistic infections of the infected individuals that are immune compromised.
The severe combined immunodeficiency mouse transplanted with human fetal thymus and liver tissues (SCID-hu Thy/Liv) is a small animal model that mimics HIV infection in humans both in terms of loss of CD4+ T lymphocytes and high viral replication. The system also enables testing in the laboratory of various drugs to combat HIV infection in vivo in a convenient model system in the absence of confounding factors found in humans. Thus, this system is a useful model for preclinical testing of anti-HIV drugs in vivo prior to undertaking clinical trials in infected humans.
Cytopenia, particularly thrombocytopenia are a major risk factor in HIV infection, heart disease, and cancer. Hematopoietic abnormalities can cause or lead to multiple cytopenia in HIV infected individuals with thrombocytopenia emerging as a major risk factor for morbidity and mortality and even more so in patients also suffering from heart conditions.
Concanavalin A (Con A)-induced hepatitis in the mouse is a well-characterized model of T cell-mediated liver diseases. This model has been extensively used as an excellent model mimicking human T cell-mediated liver diseases, such as autoimmune hepatitis ((Tiegs et al., 1992, JCI, Mizuhara H., JEM, 1994, Toyabe S, JI, 1997). A single injection of Con A is sufficient for the T cell-mediated liver injury in mice (Tiegs et al., 1992, JCI, Mizuhara H., JEM, 1994, Toyabe S, JI, 1997). Serum enzymes and histological evidence of Con A induced hepatitis is observed following 8-24 hours, as shown by elevated serum levels of ALT and AST and the occurrence of histological evidence of hepatic lesions characterized by a massive granulocytes accumulation, CD4+ T cell infiltration and an influx of a relatively small number of CD8+ T cells and hepatocyte necrosis/apoptosis (Tiegs et al., 1992, JCI, Mizuhara H., JEM, 1994, Schumann J., 2000, Am. J. Pathol., Chen et al., 2001). Recently, several investigators have implicated hepatic NKT cells in the development of Con A-induced hepatitis. Both Jα18 and CD1d-deficient mice that lack NKT cells are resistant to Con A-induced hepatic injury (Kaneko et al., 2000; Takeda et al., 2000), indicating that classical CD1d-restricted NKT cells that express the iNKT cell receptor are critically involved in the process of Con A induced hepatic injury.